1 Steinmaus Metal Toxicity.pptPublic Health Medical Officer, California Environmental Protection Agency (OEHHA)
Associate Adjunct Professor, Epidemiology, University of California, Berkeley
Assistant Adjunct Professor, Occupational and Environmental Medicine, University of California, San Francisco
No disclosures
WHAT IS A METAL? “Any of various opaque, fusible, ductile, and typically lustrous substances that are good conductors of electricity and heat, form cations by loss of electrons, and yield basic oxides and hydroxides” Webster’s Medical Currently 91 of the 118 total elements in the periodic table are classified as metals Differences between metals and non-metals is not always inherently obvious:
Copper Antimony Silver Arsenic Iron Sodium Gold Magnesium
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OTHER DEFINITIONS HEAVY METALS: •A metal of relatively high density, or of high relative atomic weight (e.g., a density at least 5 times greater than that of water). •Definitions vary widely – no consensus •Examples: cadmium, mercury, lead, chromium ALLOY: •A mixture of a metal with another metal or element •Examples: Steel: iron-carbon alloy
Brass: copper-zinc alloy Bronze: copper-tin alloy
ESSENTIAL: •Cobalt, copper, chromium, iron, magnesium, manganese, molybdenum, nickel, selenium, and zinc
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Chromium: introduction MW=52 SG=7.2 melting point=1857
Several valence states: 3 and 6 are the most commonly encountered by humans and most biologically relevant
Chromium III (chromic)
An essential nutrient involved in glucose metabolism
Deficiencies are rare: diabetes (including weight loss, neuropathy, and impaired glucose tolerance)
Chromium VI (chromate)
Cr6 is generally more toxic than Cr3
Exposures to CrVI: Ferrochrome production Ore refining Chemical and refractory processing Combustion of fossil fuels Leather tannery workers Stainless steel production, welding Chrome electroplating Portland cement Textile dyeing Glass making Wood preservatives Paint pigments
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Operation ug Cr/m3
Stainless steel welding 50-400 Chromate production 100-500 Chrome plating 5-25 Ferrochrome alloys 10-140 Chrome pigment 60-600 Leather tanning 10-50 OSHA PEL 5.0*
Ambient air (US) 0.005-0.16 Ambient (South pole) <0.001
*Implemented in 2006, was 52 ug/m3. Based on lung cancer risk
HEALTH EFFECTS OF Cr(VI)
Acute: (rare in US)
Chronic:
Skin ulcers
Lung cancer (IARC group 1)
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Changes in exposure and risk over time • Painesville Ohio Chromate Production Plant • From Proctor et al., J Exp Sc Environ Epi, 2006
N   Person- years  
Year of Hire 1940-1949 1950-1959 1960-1971  
308 215 191  
11,553 7,606 5,376  
40 25 12  
18.0 12.6 10.6  
222 198 113  
153 to 291 120 to 275 49 to 177  
Average Cr6 exposures levels by year   Year   ug/m3 Cr6   1940’s   720   1957-64   270   1965-72   39  
Lung cancer risk:
Recent issues…
Does Cr(VI) in drinking water cause cancer? PG&E plant in Hinkley, California used Cr6 as a rust inhibitor, contaminated nearby water table
• Citizens complained of multiple ailments: various cancers, skin lesions, headaches...
• PG&E eventually paid out $333 million to the citizens of Hinkley
• “Largest settlement ever paid in a direct action lawsuit in the US”
38% of municipal wells in California had detectable Cr6
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Environmental Working Group
Limited data in humans Water supplies in five rural villages near JinZhou, China contaminated by a chromium ore smelting facility
1987: Zhang, JD et al reported an increase in overall cancer mortality in these villages (interpreted from Chinese):
“Malignant tumor mortality rates (adjusted) for residents located in the polluted area were 71-93/100,000, while the tumor mortality rate in the rest of the district was 65/100,000”
“Stomach cancer mortality rates were 27-55/100,00 higher than the average for the district as a whole, with signs of increasing malignant tumor mortality rates as proximity to the pollution source increases.”
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Limited and controversial data in humans Water supplies in five rural villages near JinZhou, China contaminated by a chromium ore smelting facility
Original article from China revised (JOEM) then retracted
OEHHA redid the analysis combining cancer and population data from all five villages near the plant and compared them to cancer rates in the rest of the province
Beaumont J et al., Epidemiology 2008
Site RR 95% CI All sites 1.23 0.97-1.53 Stomach 1.69 1.12-2.44 Lung 1.78 1.03-2.87
Welling et al., Occup Environ Med 2014
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National Toxicology Program (NTP) Animal experiment of Cr6 in Water (2008)
Percent with
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CADMIUM
CADMIUM: EXPOSURE SOURCES
ØByproduct of zinc production ØCadmium electroplating ØIndustrial emissions: smelters, coal and oil fired burners… ØCommercial products (production):
• Nickel-cadmium batteries (77%) • Pigments (11%) • Electroplating (8%) • Ceramics and glass • Alloys
ØEnvironmental: smoking, foods (shellfish, liver, and kidney meats, grain cereal products, potatoes, and some leafy vegetables)
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CADMIUM TOXICITY Kidney Renal (tubular) dysfunction Increased secretion of low MW proteins: • Retinol binding proteins, β2-
microglobin, α1-macroglobulin • Can be used for screening Urinary excretion: 30 years (exceptionally long) Respiratory (inhalation of fumes or dust) Emphysema, fibrosis Cancer IARC Category 1 (1993): lung cancer
Itai-itai disease
q“It hurts, it hurts” qContamination of the Jinzu River in Toyama Prefecture, Japan qUpriver mining of silver, lead, copper, and zinc in 1910-45 qSymptoms: bone fractures, osteomalacia, osteoporosis, bone deformities, kidney failure qMechanism: Cd interfers with calcium, phosphorous and bone metabolism
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IARC summary (2012) “The results of the studies on cadmium exposure and the risk of prostate cancer are suggestive of an association, but the results are inconsistent”.
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qConsistent association, statistically significant qCase-control studies qUrinary Cd measured at the time of case-diagnosis
ZINC
Molecular weight: 97.45 Molecular formula: Zn Melting point: 419 deg C State: soft bluish white shiny metal Insoluble in water High vapor pressure Odorless
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ZINC: USES and SOURCES OF EXPOSURE Smelting of zinc ores Production of brass (zinc –copper alloy) Metal coatings Dry cell batteries Penny: 97% zinc ZINC: AN ESSENTIAL ELEMENT Enzyme function: alcohol dehydrogenase, alkaline phosphatase, carbonic anhydrase DNA and RNA polymerase: maintain nucleic acid structure of genes Deficiency: decreased production of DNA, RNA and protein Symptoms of deficiency: dermatitis, anorexia, growth retardation, poor wound healing, impaired immune function, depressed mental function
Zinc deficiency
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ZINC: TOXICITY Inhalation: Metal Fume Fever qZinc oxide fumes (welding, Zn processing, Zn-
containing alloys, galvanized steel) qSymptoms (a few hours after exposure): shortness of
breath, fatigue, chills, fever, myalgias, cough, dyspnea, leukocytosis, thirst, metallic taste and salivation
qAcute symptoms usually resolve in 1-4 days
ZINC: TOXICITY
Oral and dermal qAnemia (related to a zinc induced copper deficiency) qDecreased serum HDL
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Case #1: $22.50 in coins Case#2: supplements, 100-150 mg Zn/day produces a negative copper balance (RDA:10-15 mg/d
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Black et al. Zinc supplements and serum lipids in young adult white males. Am J Clin Nutr. 1988 Jun;47(6):970-5
Zinc and colds: 2011 Cochran Review
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Manganese (Mn) Molecular weight: 25 12th most abundant element on earth Primary use: steel production
Alloying agent: increases strength, reduces corrosion About 0.1-1%, almost all steel
Exposures: mining, ferroalloy production, alkaline battery manufacturing, steel welding, pesticides Route of exposure: inhalation (occupational), drinking water
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More subtle neurotoxicity (lower exposures) Memory, fine motor movements Exposure levels associated with neurobehavioral symptoms: ≥0.03-0.25 mg/m3 (Pattys Toxicology 2012) ACGIH TLV: 0.02 mg/m3 TWA (respirable fraction) OSHA PEL: 5 mg/m3 ceiling
Manganism Parkinsons Age of onset < 60 years old > 60 years old Symmetry of symptoms
Symmetry Asymmetry
Tremor Active or no tremor Resting tremor Response to levodopa
Poor response Good response
Normal Abnormal
Meyer-Baron M et al. Performance alterations associated with occupational exposure to manganese--a meta-analysis. Neurotoxicology. 2009 Jul;30(4):487-96.
MnInh=inhalation MnB=blood (normal 4-15 ug/L)
Oulhote et al., EHP 2012 N=375 children Quebec, Canada Age 6-13 years old Lived at house >3 mo Data on alcohol, tobacco, moms IQ, family income, lead Drinking water manganese levels
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Current US Regulations for Manganese in Water Primary MCL: none Secondary MCL: 50 ug/L* Contaminant Candidate List (CCL): yes * non-mandatory standards for cosmetics and odor
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Consumers Report November 2012: Arsenic in Rice
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Table 1. Percent of US rice products with various concentrations of inorganic arsenic (US FDA), and estimated cancer risks. Arsenic concentration
in rice (dry weight) Number
of products
ppb µg/g1 Adult (70 kg) Child (20 kg)4
ND 0 28 15% 0 0 0 0-50 0.025 14 7% 2.8 1 in 2143 1 in 612
51-100 0.075 42 22% 8.4 1 in 714 1 in 204 101-160 0.13 65 34% 14.6 1 in 412 1 in 118
>160 0.20 44 23% 22.4 1 in 268 1 in 77 1. Midpoint in this category in µg of inorganic arsenic per gram of rice (dry weight). 2. Two cups of wet or cooked rice = 112 grams of dry rice. Assumes 100% absorption. 3. Using risks estimated by the National Research Council (2). 4. Predicted by adjusting for a child’s lower bodyweight, and thus higher exposure per bodyweight.  
Arsenic in rice products sold in the US
University of Washington Study Ø 65 wines in 4 states ØAll but one exceeded US standard for arsenic in water (10 ppb) ØRange: 10 to 76 parts per billion. ØAverage: 24 ppb Ø Take home: an additional source of As in heavy wine drinkers
ARSENIC IN WINE
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1. Types of cancers that have been linked to chromium VI include all except…
A. Breast cancer B. Stomach cancer C. Lung cancer
1. Types of cancers that have been linked to chromium VI include all except…
A. Breast cancer B. Stomach cancer C. Lung cancer
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A. Itai itai disease B. Renal tubular dysfunction and
urinary secretion of low molecular weight proteins
C. Lung cancer D. All of the above
2. Health effects associated with cadmium exposure include:
A. Itai itai disease B. Renal tubular dysfunction and
urinary secretion of low molecular weight proteins
C. Lung cancer D. All of the above
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3. The health effect most commonly associated with manganese exposure is:
A. Minamta disease B. Cancer C. Neurotoxicity D. Copper deficiency
3. The health effect most commonly associated with manganese exposure is: